Summary Preterm birth and pre-eclampsia/eclampsia are leading causes of infant and maternal morbidity and mortality, yet the causes of both spontaneous preterm birth and pre-eclampsia remain unclear. There is a critical need to identify possible causal pathways as well as predictive factors for these outcomes. Because exposures are ultimately inherently chemical in nature, exposome-wide association studies (EWAS) can be conducted with untargeted analysis of small molecules in blood (`the blood exposome') from disease cases and controls using mass spectrometry. Because blood transports chemicals to and from tissues and represents a reservoir of all endogenous and exogenous chemicals in the body at a given time, the blood exposome offers a parsimonious but relatively unexplored means for interrogating biologically- relevant exposures. Our long-term goal is to identify causes of preterm birth and pre-eclampsia as well as the corresponding targets for intervention. The overall objective of this analysis is to characterize the blood exposome in cases and controls of a) spontaneous preterm birth, and b) pre-eclampsia. Our central hypothesis is that biomarkers can be identified in the first trimester that characterizes and predicts these outcomes. We will accomplish this objective by carrying out the following specific aims: 1) To determine differences in the blood exposomes of cases of spontaneous preterm birth and non-cases; 2) To determine differences in the blood exposomes of cases of pre-eclampsia and non-cases; 3) To identify the most predictive marker or set of markers for preterm birth and pre-eclampsia, and 4). To examine the relationship between known risk factors for the outcomes (race, smoking, stress) and the identified markers. We will accomplish these specific aims by performing untargeted small-molecule analysis on existing samples from the GAPPS repository, a biobank and data source with standardized data collection, case adjudication, and quality control measures. Fifty first-trimester serum samples will be obtained from cases of spontaneous preterm birth, 50 from cases of pre-eclampsia, and 100 controls. This study will lay the groundwork for larger studies of predictive markers and biological pathways leading to infant morbidity and mortality.